The ovarian hormones estradiol (E2) and progesterone (P) act in the hypothalamus (HYP) and preoptic area (POA) to ensure that the preovulatory luteinizing hormone (LH) surge coincides with reproductive behavior (lordosis), thereby maximizing reproductive success. We propose that E2 and P-dependent changes in norepinephrine (NE) synaptic activity in the HYP and POA are key mediators of the neuroendocrine integration of reproduction. We propose further that insulin-like growth factor-I (IGF-1) and its receptor (IGF-1R) mediate certain reproductive actions of E2 in the HYP-POA and engage in cross talk with NE receptors in these brain areas. The proposed research will elucidate the molecular mechanism(s) by which E2 and P interact with IGF-1 R and a1-adrenergic receptor signaling pathways in the HYP and POA and will relate these to lordosis behavior. Specific Aim 1 tests the hypothesis that IGF-1 Rs mediate E2 actions in the HYP-POA that are involved in female reproductive function via activation of phosphoinositide 3-kinase (PI3-K) or mitogen-activated protein kinase (MAPK). We will assess (a) E2 facilitation of lordosis behavior; (b) E2-induced increases in IGF-1 R density in the HYPPOA; (c) E2+P-induced coupling of a1-adrenoceptors to cGMP synthesis in the HYP-POA; and (d) E2-induced increases in spine density on ventromedial hypothalamic neurons. Specific Aim 2 tests the hypothesis that E2+P-dependent linkage of a1-adrenoceptors to cGMP also results in activation of MAPK signaling in the HYP and POA. Specific Aim 3 tests the hypothesis that in the HYP-POA of E2-treated rats, P switches a1-adrenoceptor signaling to synthesis of cGMP, which mediates NE facilitation of lordosis, by elevating intracellular calcium. We will determine whether a1-adrenoceptors stimulate cGMP formation by activating: (a) extracellular calcium influx via N and/or L-type calcium channels; (b) intracellular calcium mobilization from the endoplasmic reticulum; (c) release of ryanodine-sensitive calcium stores; and/or (d) growth factor-regulated kinases such as src or P13-K. Specific Aim 4 will determine how IGF-1 acutely potentiates a1-adrenoceptor signaling in the HYP-POA of E2-treated females and whether this is important for reproductive behavior.